Phase 3 Trials of Tapinarof Cream for Plaque Psoriasis.

BACKGROUND: Tapinarof cream is a topical aryl hydrocarbon receptor-modulating agent under investigation for the treatment of psoriasis. Tapinarof modulates the expression of interleukin-17 and the skin-barrier proteins filaggrin and loricrin. METHODS: We conducted two identical phase 3 randomized trials of tapinarof in patients with mild-to-severe plaque psoriasis. Adults with a baseline Physician's Global Assessment (PGA) score of 2 (mild) to 4 (severe) (on a scale from 0 to 4, with higher scores indicating more severe psoriasis) and a percent of total body-surface area affected of 3 to 20% were randomly assigned in a 2:1 ratio to use tapinarof 1% cream or vehicle cream once daily for 12 weeks. The primary end point, PGA response, was a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points at week 12. Secondary efficacy end points at week 12 were a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) score, a PGA score of 0 or 1, the mean change from baseline in the percent of body-surface area affected, and a reduction of at least 90% in the PASI score. Patient-reported outcomes were the mean changes from baseline to week 12 in the proportion of patients who had a decrease of at least 4 points in the Peak Pruritus Numeric Rating Scale (PP-NRS) score (range, 0 [no itch] to 10 [worst imaginable itch]), the PP-NRS total score, the Dermatology Life Quality Index total score, and the Psoriasis Symptom Diary score. RESULTS: In trials 1 and 2, a total of 692 and 674 patients, respectively, were screened, with 510 and 515 patients being enrolled. A PGA response occurred in 35.4% of the patients in the tapinarof group and in 6.0% of those in the vehicle group in trial 1 and in 40.2% and 6.3%, respectively, in trial 2 (P<0.001 for both comparisons). Results for secondary end points and patient-reported outcomes were generally in the same direction as those for the primary end point. Adverse events with tapinarof cream included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus. CONCLUSIONS: Tapinarof 1% cream once daily was superior to vehicle control in reducing the severity of plaque psoriasis over a period of 12 weeks but was associated with local adverse events and headache. Larger and longer trials are needed to evaluate the efficacy and safety of tapinarof cream as compared with existing treatments for psoriasis. (Funded by Dermavant Sciences; PSOARING 1 and 2 ClinicalTrials.gov numbers, NCT03956355 and NCT03983980, respectively.).

Topical 15% Resorcinol Is Associated with High Treatment Satisfaction in Patients with Mild to Moderate Hidradenitis Suppurativa.

BACKGROUND: Topical 15% resorcinol is commonly used in clinical practice for the treatment of nodules and abscesses in patients with hidradenitis suppurativa (HS). It has been shown to be clinically effective in some small studies, but data on satisfaction perceived by patients are lacking. The Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4 is a validated measure of patient satisfaction, evaluating four domains: effectiveness, side effects, convenience, and global satisfaction. Our objective was to obtain data from HS patients regarding resorcinol treatment satisfaction and its relationship with clinical and epidemiological variables. METHODS: We performed a cross-sectional study providing TSQM version 1.4 questionnaires to HS patients who had been prescribed topical resorcinol during the previous 24 months. RESULTS: Ninety-two patients answered the questionnaire. Eighty-five out of 92 (92.4%) were Hurley II and 7 Hurley I. The mean total score was 317.5 out of 400 (71.0 points in effectiveness, 93.6 in side effects, 79.3 in convenience, and 73.2 in global satisfaction). Total score was higher in men than in women (329.7 vs. 311.6, p = 0.026) and higher scores on convenience were seen in patients who were not overweight or obese (86.9 vs. 77.1, p = 0.016). Most patients (65, 70.6%) denied having any side effect. 78 (84.8%) of the patients would recommend the treatment. CONCLUSION: The results of this study suggest that HS patients treated with resorcinol 15% are very satisfied with this treatment.

A phase 2b, randomized clinical trial of tapinarof cream for the treatment of plaque psoriasis: Secondary efficacy and patient-reported outcomes.

BACKGROUND: Tapinarof cream is a topical therapeutic aryl hydrocarbon receptor modulating agent under investigation for treatment of psoriasis and atopic dermatitis. METHODS: In a phase 2b, double-blind, vehicle-controlled study, adults with plaque psoriasis were randomized to tapinarof cream 0.5% or 1% once or twice daily or vehicle once or twice daily for 12 weeks with 4-week follow-up. Efficacy outcomes included Physician Global Assessment (PGA) scores, change in PGA and total target lesion grading scores, and proportion of patients achieving ≥50%, ≥75%, and ≥90% reductions in the Psoriasis Area and Severity Index scores from baseline (PASI50, PASI75, and PASI90). RESULTS: At week 12, improvements were observed in all tapinarof groups vs vehicle in PGA response, change in PGA and total target lesion grading scores, PASI50 (71%-92% vs 10%-32%), PASI75 (46%-65% vs 5%-16%), and PASI90 (18%-40% vs 0%); all differences were statistically significant with tapinarof 1% once daily. Tapinarof responses were apparent from week 2, with significant efficacy at week 8 maintained through week 16. Most adverse events were mild or moderate. LIMITATIONS: The analyses reported require confirmation in larger prospective studies. CONCLUSIONS: Tapinarof may represent an important advance in the development of topical medicines for treatment of psoriasis.

Efficacy and patient-reported outcomes from a phase 2b, randomized clinical trial of tapinarof cream for the treatment of adolescents and adults with atopic dermatitis.

BACKGROUND: Tapinarof is a topical therapeutic aryl hydrocarbon receptor modulating agent under investigation for atopic dermatitis (AD) and psoriasis treatment. METHODS: A phase 2b, double-blind, vehicle-controlled study randomly assigned adolescents and adults with AD to receive tapinarof cream 0.5%, 1%, or vehicle, once or twice daily, for 12 weeks with a 4-week follow-up. Outcomes included Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI), body surface area affected, pruritus numeric rating scale scores, patients' impressions of AD and pruritus symptom severity, and Patient-Oriented Eczema Measure (POEM) scores. RESULTS: Overall, 191 of 247 randomized patients completed the study. Week 12 IGA responses were higher in the tapinarof groups versus the vehicle group, reaching statistical significance with tapinarof 1% twice daily, ≥75%/90% improvement in EASI from baseline were significantly higher in the tapinarof groups (except 0.5% once daily and 0.5% twice daily), EASI scores were significantly improved in all tapinarof groups, and body surface area affected was significantly reduced in the tapinarof groups (except 0.5% twice daily). More patients reported AD and pruritus symptom severity as very/moderately improved in tapinarof groups, and POEM improvements were observed in all groups. Most adverse events were mild or moderate. LIMITATIONS: Larger prospective studies are required to confirm the reported analyses. CONCLUSIONS: Tapinarof is a potential important advance in topical medicine development for AD.

Read-across can increase confidence in the Next Generation Risk Assessment for skin sensitisation: A case study with resorcinol.

Historically skin sensitisation risk assessment for cosmetic ingredients was based on animal models, however regulatory demands have led to Next Generation Risk Assessment (NGRA), using data from New Approach Methodologies (NAM) and Defined Approaches (DA). This case study was meant to investigate if the use of resorcinol at 0.2% in a face cream was safe and a maximum use concentration could be defined. The NAM data and DA predictions could not provide sufficient confidence to determine a point of departure (POD). Therefore, the application of read-across was explored to increase the level of confidence. Analogue searches in various tools and databases using "mode of action" and "chemical structural features" retrieved 535 analogues. After refinement by excluding analogues without a defined structure, similar reactivity profile and skin sensitisation data, 39 analogues remained. A final selection was made based on three approaches: expert judgment, chemical similarity or Local Lymph Node Assay data (LLNA). All read-across approaches supported a moderate potency. A POD derived from the LLNA EC3 of 3.6% was determined leading to a favourable NGRA conclusion and a maximum use concentration of 0.36%. This was supported by a traditional risk assessment based on the available animal data for resorcinol.

Topical Agents Currently in Phase II or Phase III Trials for Atopic Dermatitis.

Mild to moderate atopic dermatitis (AD) occurs frequently in children and adults and is usually managed through the use of pharmacologic treatments, such as topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs), and good skin care practices. As chronic TCS or TCI can lead to the development of adverse effects, there is a need for safe, alternative treatments for patients with resistant AD. A systemic literature review was performed to examine the safety and efficacy of topical agents currently in phase II and phase III clinical trials for AD. Our team searched the databases, PubMed, Google Scholar, and ClinicalTrials.gov, on March 2020 for studies pertaining to the use of topical agents in AD. Key words included each drug (tapinarof, crisaborole, ARQ-151 cream, ruxolitinib) or "topical agents"; combined with "atopic dermatitis"; Articles published within the last 5 years were included as references. References within retrieved articles were also reviewed to identify potentially missed studies. A total of 24 articles were included in this review. Tapinarof, crisaborole, and ruxolitinib lead to statistically significant improvements in multiple disease severity scores. ARQ-151 cream achieved statistical significance in secondary endpoints, including vIGA-AD and EASI-75, but not in the primary endpoint of the study. All topical agents were well-tolerated by study participants. The findings demonstrate that tapinarof, crisaborole, ARQ-151 cream, and ruxolitinib are safe, effective treatment options for patients with mild to moderate AD. J Drugs Dermatol. 2020;19(10):956-959. doi: 10.36849/JDD.2020.5214.

Phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of plaque psoriasis.

BACKGROUND: There is a significant need for novel, safe, and efficacious topical treatments for psoriasis. OBJECTIVE: We assessed the safety and efficacy of tapinarof in a new cream formulation at 2 concentrations and with 2 application frequencies in adults with psoriasis. METHODS: Double-blind, vehicle-controlled, randomized, 6-arm trial (1:1:1:1:1:1) in adults, with psoriasis with body surface involvement ≥1% and ≤15% and Physician Global Assessment (PGA) score ≥2 at baseline. Primary endpoint included PGA of 0 or 1 at week 12 and a 2-grade improvement from baseline. Additional analyses included assessment of ≥75% improvement of Psoriasis Area and Severity Index and mean percent change in Psoriasis Area and Severity Index and body surface area involvement. RESULTS: Treatment success defined by PGA 0 or 1 and a 2-grade improvement at week 12 was statistically significantly higher (at a .05 significance level) in the tapinarof groups (65% [1% twice daily], 56% [1% once daily], 46% [0.5% twice daily], and 36% [0.5% once daily]) than in the vehicle groups (11% [twice daily] and 5% [once daily]) and was maintained for 4 weeks posttreatment. Treatment-emergent adverse events were more frequent in patients treated with tapinarof (85/152, 56%) than vehicle (19/75, 25%) and mild-to-moderate in intensity. Severe treatment-emergent adverse events were reported in all tapinarof groups except the 0.5% once daily group. LIMITATIONS: Large confirmation trials are needed. CONCLUSIONS: Tapinarof cream is efficacious and well tolerated in adult patients with psoriasis.

Impact of phenolic compounds on Meloidogyne incognita in vitro and in tomato plants.

Exposing second-stage juveniles (J2) of Meloidogyne incognita in vitro to a phenolic compound sometimes fails to cause J2 mortality, but in tests in vivo the same compound may reduce the infectivity and population of the nematode. This work aimed to study the effect of phenolic compounds on M. incognita through in vitro and in vivo assays. In the in vitro assay 49 phenolic compounds were screened for their toxicity to M. incognita J2. As a result, D-(-)-4-hydroxyphenylglycine, t-butylhydroquinone, L-3-(3,4-dihydroxyphenyl)alanine, sesamol, 2,4-dihydroxyacetophenone, and p-anisaldehyde increased the J2 mortality. These compounds presented, respectively, the following lethal concentrations to 50% of J2 (LC50): 365, 352, 251, 218, 210, and 85 µg/mL, while Carbofuran (positive control) had 150 µg/mL. However, none of these compounds were efficient in controlling the nematode in inoculated tomato plants, even when 2.77-fold of their LC50 were used. Although inactive in the in vitro test at 500 µg/mL, hydroquinone (3.5 mg per plant) reduced M. incognita population and galls by up to 99% to levels similar to the nematicide Carbofuran (1.2 mg per plant). Additionally, hydroquinone increased the root weight when compared to the negative and positive controls, water/NaOH and Carbofuran, respectively. In this study, we showed that some phenolic compounds, hydroquinone in particular, revealed a potential new option for the control of M. incognita.

Hybrid polymeric microspheres for enhancing the encapsulation of phenylethyl resorcinol.

Phenylethyl resorcinol (PR) has been known to allow the whitening effect by inhibiting formation of tyrosinase. PR has solubility of 4.05 ± 0.02 mg/g for water and log P of 3.017, proposed an amphiphilic substance. Hybrid PLGA microspheres with oil (HPMSs) have been used to improve encapsulation efficiency (EE) of hydrophilic molecules and control the release of them. The solubility (618.3 ± 22.29 mg/g) of PR was the highest in CapryolTM 90. The formulations (F6 and F`6) were selected after evaluation with EE and the released % (w/w) at 8 h. HPMSs showed 40% (w/w) increase of EE compared to that in CPMSs. Retention study on rat skin at 12 h resulted in that PR of HPMSs was remained more than that of CPMSs in dermal layer forming the melanin. HPMSs showed 1.4-fold increase of tyrosinase inhibition significantly in melanoma cells than that of the PR solution at 24 h.

Enhanced Function and Overexpression of Metabotropic Glutamate Receptors 1 and 5 in the Spinal Cord of the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis during Disease Progression.

Glutamate (Glu)-mediated excitotoxicity is a major cause of amyotrophic lateral sclerosis (ALS) and our previous work highlighted that abnormal Glu release may represent a leading mechanism for excessive synaptic Glu. We demonstrated that group I metabotropic Glu receptors (mGluR1, mGluR5) produced abnormal Glu release in SOD1G93A mouse spinal cord at a late disease stage (120 days). Here, we studied this phenomenon in pre-symptomatic (30 and 60 days) and early-symptomatic (90 days) SOD1G93A mice. The mGluR1/5 agonist (S)-3,5-Dihydroxyphenylglycine (3,5-DHPG) concentration dependently stimulated the release of [3H]d-Aspartate ([3H]d-Asp), which was comparable in 30- and 60-day-old wild type mice and SOD1G93A mice. At variance, [3H]d-Asp release was significantly augmented in 90-day-old SOD1G93A mice and both mGluR1 and mGluR5 were involved. The 3,5-DHPG-induced [3H]d-Asp release was exocytotic, being of vesicular origin and mediated by intra-terminal Ca2+ release. mGluR1 and mGluR5 expression was increased in Glu spinal cord axon terminals of 90-day-old SOD1G93A mice, but not in the whole axon terminal population. Interestingly, mGluR1 and mGluR5 were significantly augmented in total spinal cord tissue already at 60 days. Thus, function and expression of group I mGluRs are enhanced in the early-symptomatic SOD1G93A mouse spinal cord, possibly participating in excessive Glu transmission and supporting their implication in ALS. Please define all abbreviations the first time they appear in the abstract, the main text, and the first figure or table caption.

Characterization and topical delivery of phenylethyl resorcinol.

OBJECTIVE: Phenylethyl resorcinol (PR) has been used widely in the personal care industry as a novel skin lightening ingredient. Surprisingly, there is only limited information describing the physicochemical properties of this active. Therefore, the primary objective of this study was to perform a comprehensive characterization of PR. A secondary objective was to investigate the delivery of this molecule to mammalian skin. METHODS: Phenylethyl resorcinol was characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and nuclear magnetic resonance (NMR). A new high-performance liquid chromatographic (HPLC) method for analysis of PR was developed and validated. The log P (octanol water partition coefficient), value, solubility and short-term stability of PR in a series of vehicles were also determined using HPLC. The evaporation of the selected vehicles was examined using dynamic vapour sorption (DVS). The permeation profiles of PR were investigated under finite dose conditions in porcine and human skin. RESULTS: The melting point of PR was determined to be 79.13 °C and the measured log P (octanol water partition coefficient) at 21 °C was 3.35 ± 0.03. The linearity of the HPLC analytical method was confirmed with an r2 value of 0.99. Accuracy of the method was evaluated by average recovery rates at three tested concentrations, and the values ranged from 99 to 106%. The limit of detection (LOD) and limit of quantification (LOQ) were 0.19 and 0.57 µg mL-1 , respectively. The solubility of PR in PG, DMI, glycerol was within the range of 367 to 877 mg mL-1 . The stability of PR in tested solvents was also confirmed by the 72 h stability studies. From the DVS studies, 70-125% of applied formulations were recovered at 24 h. The permeation through porcine skin at 24 h ranged from 4 to 13 µg cm-2 , while the corresponding amounts of PR delivered through human skin were 2 to 10 µg cm-2 . CONCLUSION: The physicochemical properties of PR confirm it is suitable for dermal delivery. In this study, propylene glycol was the most promising vehicle for PR delivery to human skin. Future work will expand the range of vehicles studied and explore the percutaneous absorption from more complex formulations.

OBJECTIF: Le phényléthyl résorcinol (PR) est largement utilisé dans le secteur des soins personnels comme ingrédient éclaircissant pour la peau. Pour autant, on ne dispose que d'informations limitées concernant les propriétés physicochimiques de ce principe actif. C'est pourquoi cette étude avait pour objectif principal de réaliser une caractérisation exhaustive du PR. Son objectif secondaire était d'étudier l'administration de cette molécule à la peau de mammifères. MÉTHODES: Le phényléthyl résorcinol a été caractérisé par calorimétrie différentielle à balayage (CDB), analyse thermogravimétrique (ATG) et par résonance magnétique nucléaire (RMN). Pour analyser le PR, une nouvelle méthode de chromatographie liquide à haute performance (CLHP) a été développée et validée. On s'est servi de la CLHP pour déterminer les propriétés suivantes du PR : log P (coefficient de partage octanol/eau), valeur, solubilité et stabilité à court terme du PR dans plusieurs véhicules. L'évaporation des véhicules sélectionnés a été examinée par sorption de vapeur dynamique (DVS). Les profils de perméabilité du PR ont été étudiés dans des conditions de dose finie dans des peaux porcine et humaine. RÉSULTATS: On a pu déterminer que le point de fusion du PR était de 79,13 °C et le log P (coefficient de partage octanol/eau) à 21 °C était de 3,35 ± 0.03. La linéarité de la méthode analytique de la CLHP a été confirmée avec une valeur r2 de 0,99. L'exactitude de la méthode a été évaluée par les taux moyens de récupération à trois concentrations testées, avec des valeurs résultantes comprises entre 99 et 106 %. La limite de détection (LD) et la limite de quantification (LQ) ont été déterminées à 0,19 et 0,57 µg/ml_ 1, respectivement. La solubilité du PR dans le PG, le DMI et le glycérol reste dans une plage comprise entre 367 et 877 mg/ml _ 1. La stabilité du PR dans les solvants testés a également pu être confirmée par les études de stabilité à 72 h. Parmi les formulations appliquées lors des études de DVS, 70 à 125 % de celles-ci ont été récupérées à 24 h. La pénétration par la peau porcine à 24 h était comprise entre 4 et 13 µg/cm_ 2, tandis que les quantités de PR correspondantes délivrées à travers la peau humaine étaient de 2 à 10 µg/cm_ 2. CONCLUSION: Les propriétés physicochimiques du PR confirment qu'il est adapté à l'administration dermique. Dans le cadre de cette étude, le propylène glycol est apparu comme le véhicule le plus prometteur pour l'administration de PR dans la peau humaine. De futurs travaux étudieront davantage de véhicules et examineront l'absorption percutanée lors de l'emploi de formulations plus complexes.

In situ biodistribution and residency of a topical anti-inflammatory using fluorescence lifetime imaging microscopy.

BACKGROUND: GSK2894512 is a topically delivered investigational drug being developed for treatment of atopic dermatitis and psoriasis. OBJECTIVES: To investigate, in a phase I clinical trial, the spatial biodistribution and residency of GSK2894512 within the epidermis and dermis of healthy human participants noninvasively using fluorescence lifetime imaging microscopy (FLIM). METHODS: Two topical drug formulations containing GSK2894512 1% were applied to the right and left forearms of six participants for seven consecutive days, followed by seven days of observation for residency. FLIM images were obtained daily throughout the study, approximately every 24 h. During the treatment phase of the study, images were collected from each participant pretreatment, reflecting the residual dose from the previous day. Three punch biopsies from each participant of one formulation was obtained from the treated region during the post-treatment follow-up period between days 8 and 14 for comparison with FLIM results. RESULTS: Cellular and subcellular features associated with different epidermal and dermal layers were visualized noninvasively, down to a depth of 200 µm. Results yielded three-dimensional maps of GSK2894512 spatial distribution and residency over time. This fluorescence data provided a marker that was used as a monitor for day-to-day variance of drug presence and residency postapplication. CONCLUSIONS: The results suggest FLIM could be a viable alternative to skin biopsies without the usual patient discomfort and limitations, thereby enabling the direct measurement of skin distribution through longitudinal monitoring. These results are the first step in establishing the unique capabilities that multiphoton imaging could provide to patients through noninvasive drug detection.

Orcinol Glucoside Loaded Polymer - Lipid Hybrid Nanostructured Lipid Carriers: Potential Cytotoxic Agents against Gastric, Colon and Hepatoma Carcinoma Cell Lines.

PURPOSE: Orcinol glucoside (OG) - loaded nanostructured lipid carrier (NLC), coated with polyethylene glycol-25/55-stearate (PEG-25/55-SA), were explored for delivering OG to improve in vitro cytotoxicity against gastrointestinal tract (GIT), colon and hepatoma carcinoma cell lines. It is being expected that the PEGylated formulations would possess the sustainability in withstanding the adverse physiological extremities like the most significant metabolic activities and phase I / II enzymatic activities in the intestines. METHODS: NLCs were prepared using tristearin, oleic acid and PEG-25/55-stearate by hot homogenization-ultrasonic dispersion; characterized by DLS, TEM, SEM, AFM, entrapment efficiency and drug loading capacity studies. RESULTS: NLC diameter ranged from 160 to 230 nm with negative zeta potential of -8 to -20 mV. TEM/SEM and AFM studies suggest spherical and smooth surface morphologies. Differential scanning calorimetry studies reveal the loss of crystallinity when OG was incorporated into the NLC. NLCs showed initial burst release, followed by sustained release of OG. PEG-NLC exhibited superior anticancer activity against GIT and also in hepatoma cancer cell lines. CONCLUSIONS: This is the first report demonstrating a practical approach for possible oral delivery of OG in GIT and targeting hepatoma cancer, warranting further in vivo studies for superior management of GIT cancer.

HSP90 inhibitor NVP-AUY922 induces cell apoptosis by disruption of the survivin in papillary thyroid carcinoma cells.

Heat shock protein 90 (HSP90) is a molecular chaperone required for maintaining the stability and function of signal proteins that plays an important role in promoting the growth and survival of cancer cells. The incidence of papillary thyroid carcinoma (PTC) has been increasing in recent years. The effect of the novel non-geldanamycin HSP90 inhibitor NVP-AUY922 on apoptosis of papillary thyroid carcinoma cells has not been investigated. The influence of AUY922 on the survival of PTC cell lines K1 and IHH4 was evaluated. Cell viability was determined by cell counting kit method. Cell apoptosis was assessed by flow cytometry and western blotting and the potential mechanism was evaluated by western blotting and immunoprecipitation. Overexpression plasmid was transfected by Lipofectamine 2000 method. In K1 and IHH4 cell lines, after the treatment of AUY922, cell viability decreased, and the proportion of apoptosis cells increased. AUY922 caused the cleavage of PARP and caspase-3 proteins, and altered expression of survivin, which was a client protein of HSP90. In AUY922-treated cells, overexpression of survivin attenuated growth inhibition and cell apoptosis. The results indicate that AUY922 induces apoptotic cell death in PTC cells. Moreover, our findings demonstrate that AUY922 induced apoptosis by downregulating the expression of survivin protein in PTC cells.

Enhanced Transdermal Delivery by Combined Application of Dissolving Microneedle Patch on Serum-Treated Skin.

Dissolving microneedle (DMN), a transdermal drug delivery system in which drugs are encapsulated in a biodegradable polymeric microstructure, is designed to dissolve after skin penetration and release the encapsulated drugs into the body. However, because of limited loading capacity of drugs within microsized structures, only a small dosage can be delivered, which is often insufficient for patients. We propose a novel DMN application that combines topical and DMN application simultaneously to improve skin permeation efficiency. Drugs in pretreated topical formulation and encapsulated drugs in DMN patch are delivered into the skin through microchannels created by DMN application, thus greatly increasing the delivered dose. We used 4-n-butylresorcinol to treat human hyperpigmentation and found that sequential application of serum formulation and DMNs was successful. In skin distribution experiments using Alexa Fluor 488 and 568 dyes as model drugs, we confirmed that the pretreated serum formulation was delivered into the skin through microchannels created by the DMNs. In vitro skin permeation and retention experiments confirmed that this novel combined application delivered more 4-n-butylresorcinol into the skin than traditional DMN-only and serum-only applications. Moreover, this combined application showed a higher efficacy in reducing patients' melanin index and hyperpigmented regions compared with the serum-only application. As combined application of DMNs on serum-treated skin can overcome both dose limitations and safety concerns, this novel approach can advance developments in transdermal drug delivery.

Development and validation of an ultraviolet-visible spectrophotometric method for determination of phenylethyl resorcinol in new topical nanoemulsions.

OBJECTIVE: To develop a rapid, simple and efficient ultraviolet-visible (UV-vis) spectrophotometric method for the quantification of phenylethyl resorcinol (PR), a potent skin-lightening agent, incorporated into new topical nanoemulsions, and to validate this method according to International Commission for Harmonization (ICH) guidelines. METHODS: UV-vis spectrophotometric method for quantification of PR in new topical nanoemulsions was developed and validated in terms of specificity, linearity, sensitivity, precision and accuracy. The method was applied to determine PR content (extraction recoveries) in the nanoemulsions and entrapment efficiencies. RESULTS: The calibration curve for PR was linear in the range of 10-60 µg mL-1 , with a determination coefficient (r2 ) which is higher than 0.999. The limit of detection (LOD) and limit of quantitation (LOQ) were 1.55 and 4.69 µg mL-1 , respectively. The method was shown to be specific, precise [intraday, interday and reproducibility levels relative standard deviation < 3%] and accurate (between 91.90 ± 1.28% and 104.73 ± 0.60%). The extraction recoveries of PR in nanoemulsions were 97.07%, 96.64% and 103.54% at concentrations of 3, 6 and 9 mg mL-1 , respectively. The entrapment efficiencies were nearly 100%, which agrees with the oil core location of PR in nanoemulsions. CONCLUSION: This developed method was confirmed to be rapid, simple, cost-effective, specific, precise, accurate and suitable for determination of PR content in nanoemulsions and entrapment efficiencies.

A Phase 2 Study of the Hsp90 Inhibitor AUY922 as Treatment for Patients with Refractory Gastrointestinal Stromal Tumors.

BACKGROUND: AUY922 is an inhibitor of heat shock protein 90 (Hsp90). Hsp90 inhibitors induce kit degradation in preclinical gastrointestinal stromal tumor (GIST) models. This trial was designed to determine the progression-free survival (PFS) of patients with GIST refractory to or intolerant of imatinib and sunitinib. METHODS: Eligible patients received AUY922 70 mg/mg(2) by intravenous (IV) infusion on days 1, 8, and 15 of 21-day cycles. Treatment continued until progression or unacceptable toxicity. RESULTS: Between December 2011 and January 2015, 25 patients were enrolled (median age, 63 years; 56% male) and received a median of 2 cycles (range: 1-12) of AUY922 treatment. Thirty-four patients were planned, but enrollment was stopped early due to slow accrual. Median PFS was 3.9 months (95% CI: 2.5, 5.3) and median OS was 8.5 months (95% CI: 5.2, 16.7). Radiographic response was evaluated in 21 patients; one patient achieved PR (4%) with another 15 having best response of stable disease (60%). The most common treatment-related adverse event was diarrhea (60% all grades). Reversible ocular toxicities that resulted in drug hold (24%) or reduction (8%) were also observed. CONCLUSION: AUY922 produced a median PFS which compares favorably to historical controls of placebo (6 weeks) for patients refractory to treatment with imatinib. While diarrhea and ocular toxicities were common, the majority of patients received treatment until disease progression.

Use of a dose-response model to guide future clinical trial of benvitimod cream to treat mild and moderate psoriasis.

OBJECTIVE: To investigate the time-dose-response relationship of benvitimod cream after topical administration in patients with mild and moderate psoriasis vulgaris for dosage regimen exploring. METHODS: 36 patients with mild and moderate psoriasis vulgaris were randomly assigned to receive 0.5%, 1.0%, 1.5%, and 0% (placebo) benvitimod cream of 30 g/1.7 m2 twice daily for 6 weeks. The primary efficacy outcome was the proportion of patients achieving more than 75% change of the psoriasis area and severity index (PASI 75) from baseline. A longitudinal Emax model was established using the NONMEM method, and then applied to try to find an appropriate dose for following trials. RESULTS: In the final time-dose-response model, the primary outcome at week 6 of PASI 75 of the 0.5%, 1.0%, and 1.5% benvitimod cream was 31%, 63%, and 75%, respectively, demonstrating that the 1.0% benvitimod cream was an appropriate dose for the next trial. The time parameters of ET50 and ET90 were 15 and 69 days for 1.0% benvitimod cream, indicating that the maximum efficacy of PASI change rate was obtained at approximately week 10. The accuracy of PASI change rate by extrapolation prediction was limited at week 10, so the treatment period should be longer in future trials. CONCLUSIONS: The established dose-response model could well describe the relationship between PASI change rate and doses of benvitimod cream in patients with mild and moderate psoriasis vulgaris. This modeling approach may help choose 1.0% benvitimod cream twice daily as a dosage regimen in following clinical trials.

A comparison of potency differences among thyroid peroxidase (TPO) inhibitors to induce developmental toxicity and other thyroid gland-linked toxicities in humans and rats.

The potencies of resorcinol, 6-propylthiouracil (PTU) and methimazole (MMI) for inducing developmental toxicity and neurotoxicity were compared in pregnant rats, regarded as valid model for human thyroid toxicity. Profound differences on maternal thyroid hormone levels (THs), maternal toxicity as well as developmental and neurotoxicity sequelae occurred. Resorcinol affected none of those end points. PTU and MMI caused significant effects. Therapy with either PTU or MMI during the first trimester of human pregnancy can cause reductions of maternal THs, accompanied by disruptions of prenatal development. Clinical MMI studies show sporadic evidence of teratogenic effects, with equivocal relation to thyroid peroxidase (TPO) inhibition. In recent decades no MMI associated prenatal toxicity has been reported, an outcome possibly related to carefully managed therapy. Orally administered resorcinol was rapidly absorbed, metabolized and excreted and was undetectable in the thyroid. In contrast, PTU or MMI accumulated. Resorcinol's potency to inhibit TPO was profoundly lower than that of PTU or MMI. Quantum chemical calculations may explain low resorcinol reactivity with TPO. Thus, distinctions in the target organ and the TPO inhibitory potency between these chemicals are likely contributing to different reductions of maternal THs levels and affecting the potency to cause developmental toxicity and neurotoxicity.